CN102639715A - Method and apparatus for prediction of pharmacological efficacy of humanized anti-TNF[alpha]antibody drug on rheumatoid arthritis - Google Patents
Method and apparatus for prediction of pharmacological efficacy of humanized anti-TNF[alpha]antibody drug on rheumatoid arthritis Download PDFInfo
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Abstract
A method for predicting the pharmacological efficacy of a humanized anti-TNF[alpha] antibody drug on rheumatoid arthritis, comprising the steps of: measuring the content of at least one of ADAMTS4 and ADAMTS5 in a sample from a subject; and determining whether or not the humanized anti-TNF[alpha] antibody drug is effective on rheumatoid arthritis by employing, as a measure, the content of at least one of ADAMTS4 and ADAMTS5 measured in the preceding step.
Description
Technical field
The present invention relates to be index from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample, prediction humanization anti-TNF alpha antibody drug is to the drug effect Forecasting Methodology and the drug effect prediction unit of rheumatoid arthritis.
Background technology
In recent years, the biotechnological formulation of target tumor necrosin (TNF α) has been used to rheumatoid arthritis, and their drug effect is approved.Adalimumab (Adalimumab; ADA) be to form the also biotechnological formulation of target TNF α, use the clinical index that is called as disease activity degree scoring (DAS28) to find that it suppresses rheumatoid arthritis (RA) mobility by full-length human anti-TNF alpha monoclonal antibody.In addition, reported that adalimumab not only suppresses the rheumatoid arthritis mobility, also suppressed the destruction of bone relevant with rheumatoid arthritis.
But,, also have the invalid rheumatoid arthritis of adalimumab although this significant drug effect is arranged.In addition; Adalimumab is easy to cause the adverse side effect like transmissible diseases such as pneumocystis carinii pneumonia and pulmonary tuberculosis owing to having, through the drug effect of prediction adalimumab before administration, and can be with the really effective illness example of adalimumab administration;, can also prevent unnecessary spinoff simultaneously.
Report is arranged so far about identifying trial like the drug effect predictor (with reference to non-patent literature 1) of adalimumab biotechnological formulation.In above-mentioned report, reported; At the administration adalimumab after 12 weeks; Through using dna microarray and algorithm that the difference of the gene expression profile in effective patient with rheumatoid arthritis of adalimumab and the invalid patient with rheumatoid arthritis of adalimumab is analyzed, the combination of 439 kinds of genes is invalid relevant with adalimumab.
Yet this method can only be retrospective test at most, not the drug effect of quantization means adalimumab.Therefore, present present situation is not obtain as yet identifying in the identifiable reliable adalimumab drug effect predictor of prospective trial.
Known, ADAMTS (dissociate element and metalloprotease with thrombospondin motif (motif)) 4 is the aggrecanase enzyme (aggrecanase) relevant with cartilage destruction that belongs to ADAMTS family with ADAMTS5.Special, reported that on degenerative osteoarthritis Muridae model the disappearance of ADAMTS5 suppresses cartilage destruction.
Yet, ADAMTS4 and ADAMTS5 one of at least content and still do not know to the cognation between the drug effect of the humanization anti-TNF alpha antibody drug of rheumatoid arthritis.
The prior art document
Non-patent literature
People such as non-patent literature 1:Badot V, Arthritis Research Therapy 11, R57,2009
Summary of the invention
Invent problem to be solved
The present invention is intended to solve above-mentioned each problem of the prior art and reaches following purpose.Promptly; The object of the present invention is to provide a kind of drug effect Forecasting Methodology and drug effect prediction unit of predicting humanization anti-TNF alpha antibody drug to rheumatoid arthritis; Said drug effect Forecasting Methodology and drug effect prediction unit can high reliability and are predicted the drug effect of humanization anti-TNF alpha antibody drug to rheumatoid arthritis easily; The mobility of rheumatoid arthritis behind the administration humanization anti-TNF alpha antibody drug can also be predicted, thereby and unnecessary spinoff can be prevented through patient's administration that said medicine is had an effect to humanization anti-TNF alpha antibody drug comparatively reliably.
Solve the means of problem
In order to address the above problem, the result that the inventor has carried out extensive studies obtains following opinion.That is, ADAMTS4 and ADAMTS5 content one of at least is high more in the peripheral blood sample of patient with rheumatoid arthritis before the administration adalimumab, and then adalimumab is to the good more opinion of drug effect of rheumatoid arthritis.Can not have prospective trial to disclose through measuring the content one of at least of ADAMTS4 and ADAMTS5 in the blood sample before the administration adalimumab and predict the drug effect of adalimumab, therefore, this be the newly discovered by inventor's acquisition.
Need to prove, said " retrospective test " be meant processing in the past with present data, and " prospective trial " is meant the test of the phenomenon that observation takes place from now on.Because retrospective test is that known item is handled, thereby comprises investigator's prejudice easily, and for this; Prospective trial is not owing to still know the result; Thereby do not have investigator's prejudice, and can obtain result more reliably, more excellent on the one hand from this.
The present invention is that the contriver obtains based on above opinion, and is as solving above-mentioned in-problem means, as follows.That is:
< 1>a kind of humanization anti-TNF alpha antibody drug is characterised in that to comprise the steps: to the drug effect Forecasting Methodology of rheumatoid arthritis
Measurement is from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample; And
Whether as index, it is effective to said experimenter's rheumatoid arthritis to estimate said humanization anti-TNF alpha antibody drug with ADAMTS4 and ADAMTS5 content one of at least.
< 2>according to the drug effect Forecasting Methodology of < 1>described humanization anti-TNF alpha antibody drug to rheumatoid arthritis, wherein, said humanization anti-TNF alpha antibody drug is adalimumab (ADA).
< 3>according to the drug effect Forecasting Methodology of < 1>or < 2>described humanization anti-TNF alpha antibody drug to rheumatoid arthritis; Wherein, said is ADAMTS4mRNA and ADAMTS5mRNA expression contents one of at least from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample.
< 4 >, wherein, measure said ADAMTS4mRNA and ADAMTS5mRNA expression amount one of at least through the PCR in real time method according to < 3>described humanization anti-TNF alpha antibody drug drug effect Forecasting Methodology to rheumatoid arthritis.
< 5>a kind of humanization anti-TNF alpha antibody drug is characterized in that to the drug effect prediction unit of rheumatoid arthritis, comprising:
Measuring unit, said measuring unit are measured the content one of at least from ADAMTS4 and ADAMTS5 in experimenter's the sample; And
Evaluation unit, whether as index, it is effective to said experimenter's rheumatoid arthritis to estimate said humanization anti-TNF alpha antibody drug with ADAMTS4 and ADAMTS5 content one of at least for said evaluation unit.
< 6>according to the drug effect prediction unit of < 5>described humanization anti-TNF alpha antibody drug to rheumatoid arthritis, wherein, said humanization anti-TNF alpha antibody drug is adalimumab (ADA).
< 7>according to the drug effect prediction unit of < 5>or < 6>described humanization anti-TNF alpha antibody drug to rheumatoid arthritis; Wherein, said is ADAMTS4mRNA and ADAMTS5mRNA expression amount one of at least from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample.
< 8 >, wherein, measure said ADAMTS4mRNA and ADAMTS5mRNA expression amount one of at least through the PCR in real time method according to < 7>described humanization anti-TNF alpha antibody drug drug effect prediction unit to rheumatoid arthritis.
The invention effect
According to the present invention; Drug effect Forecasting Methodology and the drug effect prediction unit of a kind of humanization anti-TNF alpha antibody drug to rheumatoid arthritis can be provided; Said drug effect Forecasting Methodology and said drug effect prediction unit can solve above-mentioned each problem of the prior art and achieve the above object; Can high reliability and predict the drug effect of humanization anti-TNF alpha antibody drug easily to rheumatoid arthritis; The mobility of rheumatoid arthritis behind the administration humanization anti-TNF alpha antibody drug can also be predicted, thereby and unnecessary spinoff can be prevented through patient's administration that said medicine is had an effect to humanization anti-TNF alpha antibody drug comparatively reliably.
Description of drawings
Figure 1A shows that (ADAMTS4mRNA expression amount (ADAMTS4/ beta-actin) is lower than 0.3 * 10 to low dose group before the administration adalimumab
-4) and high dose group (ADAMTS4mRNA expression contents (ADAMTS4/ beta-actin) is equal to or higher than 0.3 * 10 before the administration adalimumab
-4) at the figure of the DAS28 (12w) of administration adalimumab after 12 weeks.
Figure 1B shows that (ADAMTS5mRNA expression amount before the administration adalimumab (ADAMTS5/ beta-actin) is lower than 4.0 * 10 to the administration adalimumab in low dose group after 12 weeks
-4) and high dose group (ADAMTS5mRNA expression amount (ADAMTS5/ beta-actin) is equal to or higher than 4.0 * 10 before the administration adalimumab
-4) the figure of DAS28 (12w).
Fig. 2 A is the figure that shows preceding ADAMTS4mRNA expression amount (ADAMTS4/ beta-actin) of administration adalimumab and the administration adalimumab relation that the DAS28 (12w) of diseases changes after 12 weeks.
Fig. 2 B is the figure that shows the relation of preceding ADAMTS5mRNA expression amount (ADAMTS5/ beta-actin) of administration adalimumab and administration adalimumab DAS28 (12w) variation after 12 weeks.
Embodiment
A kind of humanization anti-TNF alpha antibody drug is to the drug effect Forecasting Methodology and the drug effect prediction unit of rheumatoid arthritis
Humanization anti-TNF alpha antibody drug of the present invention comprises to the drug effect Forecasting Methodology of rheumatoid arthritis at least: measure from the step (measuring process) of the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample and with ADAMTS4 and ADAMTS5 content one of at least and estimate whether effective step (evaluation procedure) of rheumatoid arthritis that said humanization anti-TNF alpha antibody drug is directed against said experimenter as index; And as required, further comprise other steps.
Humanization anti-TNF alpha antibody drug of the present invention comprises to the drug effect prediction unit of rheumatoid arthritis at least: measure the unit (measuring unit) from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample; And estimate said humanization anti-TNF alpha antibody drug to said experimenter's rheumatoid arthritis unit (evaluation unit) whether effectively as index with ADAMTS4 and ADAMTS5 content one of at least; And as required, further comprise other unit.
< measuring process and measuring unit >
Measuring process is the step of measuring from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample.
Measuring unit is the unit of measuring from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample.
-from experimenter's sample-
As above-mentioned sample from the experimenter, not special restriction can suitably be selected according to purpose, and for example, the example comprises peripheral blood, synovial membrane and synovial membrane liquid etc.Wherein, peripheral blood is owing to taking easily, so preferred.
As above-mentioned experimenter, not special restriction can suitably be selected according to purpose, and the example comprises the people.
-ADAMTS4-
Known above-mentioned ADAMTS (dissociate element and metalloprotease) the 4th with thrombospondin motif, a kind of aggrecanase enzyme relevant that belongs to ADAMTS family with cartilage destruction.
The nucleotide sequence of ADAMTS4 gene for example, is human known, and this nucleotide sequence is easy to obtain from the public database like GenBank (NCBI).For example, the nucleotide sequence of human ADAMTS4 gene can obtain according to NCBI accession number NM_005099.
-ADAMTS5-
Known above-mentioned ADAMTS (dissociate element and metalloprotease) the 5th with thrombospondin motif, a kind of aggrecanase enzyme relevant that belongs to ADAMTS family with cartilage destruction.
The nucleotide sequence of ADAMTS5 gene for example, is human known, and this nucleotide sequence is easy to obtain from the public database like GenBank (NCBI).For example, the nucleotide sequence of human ADAMTS5 gene can obtain according to NCBI accession number NM_007038.
The measurement of-content-
As measuring above-mentioned method from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample; Not special restriction; Can suitably select according to purpose, for example, the example comprises the method for measuring the mRNA expression amount and the method for measuring protein expression content etc.
As the method for measuring above-mentioned mRNA expression amount, not special restriction can suitably be selected according to purpose, and for example, the example comprises the PCR method, PCR in real time method, DNA Array Method and Northern hybrid method etc.
As the device of measuring above-mentioned mRNA expression amount, not special restriction can suitably be selected according to purpose, and for example, the example comprises the PCR device, PCR in real time device, DNA array apparatus and Northern hybrid device etc.More than device can suitably use as above-mentioned measuring unit.
As above-mentioned real-time PCR method, not special restriction can suitably not selected according to purpose, and for example, the example comprises makes working curve and based on the method (calibration curve) of this working curve quantized samples.
As the contrast dna profiling that is used for above-mentioned calibration curve; Not special restriction; Can suitably select according to purpose, for example, the example comprises from healthy subjects and obtains and all cDNA of purifying, enroll the plasmid of ADAMTS4cDNA and enroll the plasmid etc. of ADAMTS5cDNA.
Do not receive special restriction as the primer that uses in the above-mentioned real-time PCR method,, can suitably select according to purpose so long as ADAMTS4 and the ADAMTS5 primer one of at least that can increase gets final product.
Endogenous contrast as using in the above-mentioned real-time PCR method does not receive special restriction, can suitably select according to purpose, and for example, the example comprises beta-actin and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) etc.
< evaluation procedure and evaluation unit >
Whether effectively above-mentioned evaluation procedure is to estimate said humanization anti-TNF alpha antibody drug to said experimenter's rheumatoid arthritis step with ADAMTS4 and ADAMTS5 content one of at least as index.
Whether effectively above-mentioned evaluation unit is to estimate said humanization anti-TNF alpha antibody drug to said experimenter's rheumatoid arthritis unit with ADAMTS4 and ADAMTS5 content one of at least.
-humanization anti-TNF alpha antibody drug-
Do not receive special restriction as above-mentioned humanization anti-TNF alpha (tumor necrosis factor alpha) antibody drug, can suitably select according to purpose, for example, preferred adalimumab (ADA).
-index-
As These parameters, use ADAMTS4 and ADAMTS5 content one of at least.These parameters can be used the content of ADAMTS4 or the content of ADAMTS5 separately, also can and with above-mentioned both.
-estimate-
Whether effective means does not receive special restriction to rheumatoid arthritis as estimating above-mentioned humanization anti-TNF alpha antibody drug; Can suitably select according to purpose; For example; When ADAMTS4 and ADAMTS5 content one of at least in patient with rheumatoid arthritis under the more situation, it is effective to this rheumatoid arthritis patient to be evaluated as humanization anti-TNF alpha antibody drug.
As concrete example, under the situation of using ADAMTS4 content as These parameters (details are with reference to following embodiment 1), when the expression amount (ADAMTS4/ beta-actin) of ADAMTS4mRNA is 0.3 * 10
-4When above, it is effective to rheumatoid arthritis to be evaluated as humanization anti-TNF alpha antibody drug.
In addition, use ADAMTS5 content to be used as (details are with reference to following embodiment 1) under the situation of index as These parameters, when the expression amount (ADAMTS5/ beta-actin) of ADAMTS5mRNA is 4 * 10
-4When above, it is effective to rheumatoid arthritis to be evaluated as humanization anti-TNF alpha antibody drug.
Do not receive special restriction as the device that carries out above-mentioned evaluation, can suitably select according to purpose, for example, the example comprises electronic calculator (computingmachine) etc.Said apparatus can be used as evaluation unit and suitably uses.
In addition, above-mentioned evaluation can also be predicted the DAS28 behind the administration humanization anti-TNF alpha antibody drug.
Above-mentioned DAS28 is the abbreviation of disease activity degree scoring (Disease Activity Score); EULAR is in order to divide value to set up the rheumatoid arthritis mobility; Be recorded in: people such as Fransen J.; Clin Exp Rheumatol 2005,23 (Suppl.39): among the S93-S99.
Method as DAS28 behind the prediction administration humanization anti-TNF alpha antibody drug does not receive special restriction; Can suitably select according to purpose; For example, the DAS28 after can being fitted to shown in the following embodiment 1 (referring to Fig. 2 A and 2B) in the figure through expression amount one of at least and predicting administration people anti-TNF alpha antibody drug with ADAMTS4mRNA and ADAMTS5mRNA in the peripheral blood of patient with rheumatoid arthritis.
< other steps and other unit >
As the not special restriction of above-mentioned other steps, can suitably select according to purpose, for example, the example comprises through taking all factors into consideration the step that ADAMTS4 and ADAMTS5 estimate with other genes one of at least.
As the not special restriction in above-mentioned other unit, can suitably select according to purpose, for example, the example comprises through taking all factors into consideration the unit that ADAMTS4 and ADAMTS5 estimate with other genes one of at least.
-other genes-
As the not special restriction of other genes, can suitably select according to purpose.The example comprises the gene of the coding lytic enzyme outside ADAMTS4 and the ADAMTS5 and specific expressed gene etc. in the rheumatoid arthritis experimenter.
Embodiment
Describe the present invention in detail below with reference to embodiment, but the present invention is not limited to these embodiment.(embodiment 1: the content with ADAMTS4 or ADAMTS5 is predicted the validity of adalimumab (ADA) to rheumatoid arthritis as index)
With year June in June, 2008 to 2009,33 routine patients of the administration adalimumab (ADA) in the patient with rheumatoid arthritis that general practice center rheumatism immunity section of the beautiful medical university of fine jade goes to a doctor are object.
< measuring process >
The mensuration of ADAMTS4mRNA expression amount in the-peripheral blood-
Gather the peripheral blood (2.5 milliliters) of the preceding patient with rheumatoid arthritis of administration adalimumab (ADA); Inject PAXgene RNA heparin tube (registered trademark then; Japan ベ Network ト Application デ イ Star キ Application ソ Application society system) in; Use PAXgene Blood RNA Kit (registered trademark, PreAnalytiX society system) to extract total RNA.Use reversed transcriptive enzyme that above-mentioned total RNA is converted into total cDNA.With above-mentioned total cDNA is dna profiling, measures the expression amount of the mRNA of ADAMTS4 through the PCR in real time method with Taqman (registered trademark) Gene Expression Assay (Applied Biosystems society system).Need to prove that the primer and probe use the primer-probe groups in (Taqman Gene (registered trademark) Expression Assay (Hs00192708_ml, Applied Biosystems society system)).
More than resulting ADAMTS4mRNA content carry out quantification through relative ratio with beta-actin (endogenous contrast) mRNA content.
Need to prove that the primer of beta-actin and probe use the primer-probe groups in (Pre-Developed TaqMan (registered trademark) AssayReagents (Human ACTB, NM_001101, Applied Biosystems society system)).
The mensuration of the mRNA expression amount of ADAMTS5 in the-peripheral blood-
Gather the peripheral blood (2.5 milliliters) of the preceding patient with rheumatoid arthritis of administration adalimumab (ADA); Inject PAXgene RNA heparin tube (registered trademark then; Japan ベ Network ト Application デ イ Star キ Application ソ Application society system) in; Use PAXgene Blood RNA Kit (registered trademark, PreAnalytiX society system) to extract total RNA.Use reversed transcriptive enzyme that above-mentioned total RNA is converted into total cDNA.With above-mentioned total cDNA is dna profiling, measures the expression amount of the mRNA of ADAMTS4 through the PCR in real time method with Taqman (registered trademark) Gene Expression Assay (Applied Biosystems society system).Need to prove that the primer and probe use the (primer-probe groups among Taqman Gene (registered trademark) the Expression Assay (00199841_ml, Applied Biosystems society system).
More than resulting ADAMTS5mRNA content carry out quantification through relative ratio with beta-actin (endogenous contrast) mRNA content.
Need to prove that the primer of beta-actin and probe use the primer-probe groups in (Pre-Developed TaqMan (registered trademark) Assay Reagents (Human ACTB, NM_001101, Applied Biosystems society system)).
< evaluation procedure >
Each rheumatic arthritis patient's mobility, the DAS28 through administration adalimumab (ADA) after preceding and 12 weeks of administration adalimumab (ADA) estimates [DAS28 (0w), DAS28 (12w)] and estimates.
Whether (ADA) be effective about adalimumab, should the improvement standard according to the EULAR that has used DAS28, be evaluated as " reactive good ", " moderate reaction " or " reactionless ".
Need to prove that EULAR improvement standard is EULAR (EULAR) defined, is recorded in: people such as Fransen J., Clin Exp Rheumatol 2005; 23 (Suppl.39): among the S93-S99.
About the effect based on EULAR improvement standard after 12 weeks of administration adalimumab (ADA), reactivity well is 15 examples, and the moderate reaction is 11 examples, and reactionless is 7 examples.In addition, 7 routine patients get into the catabasis (DAS28 (12w)＜2.6).
Between-low dose group and high dose group first comparison (ADAMTS4)-
33 routine patient with rheumatoid arthritis about the administration adalimumab; Through by adopting the PCR in real time method as the calibration curve of contrast template, the expression amount (ADAMTS4/ beta-actin) of the mRNA of the ADAMTS4 before their the administration adalimumab is carried out quantitatively from total cDNA of healthy subjects.Then, hive off, be lower than 0.3 * 10 at the expression amount (ADAMTS4/ beta-actin) of the mRNA of ADAMTS4
-4Situation under be low dose group, and 0.3 * 10
-4Under the above situation is high dose group, and compares its DAS28 (12w), and the result shows, the DAS28 of high dose group (12w) low significantly (seeing Figure 1A).
Between-low dose group and high dose group second comparison (ADAMTS5)-
33 routine patient with rheumatoid arthritis about the administration adalimumab; Through by adopting the PCR in real time method as the calibration curve of contrast template, the expression amount (ADAMTS5/ beta-actin) of the mRNA of the ADAMTS5 before their the administration adalimumab is carried out quantitatively from total cDNA of healthy subjects.Then, hive off, be lower than 4.0 * 10 at the expression amount (ADAMTS5/ beta-actin) of the mRNA of ADAMTS5
-4Situation under be low dose group, and 4.0 * 10
-4Under the above situation is high dose group, and compares its DAS28 (12w), and the result shows, the DAS28 of high dose group (12w) low significantly (seeing Figure 1B).
--first between GR group and NGR group be (ADAMTS4) relatively--
As index, to above-mentioned low dose group and high dose group, the classification that further is divided under the situation of GR group (reactivity is well organized) and NGR group (reactionless+moderate is reacted) is as shown in table 1 with the content of ADAMTS4.
Table 1
| ADAMTS4 | GR | NGR | Amount to |
| |
6 | 1 | 7 |
| Low dose group | 9 | 17 | 26 |
| Amount to | 15 | 18 | 33 |
x
2p＝0.016
Based on the classification shown in the table 1, by following formula meter sensitivity, specificity, positive prediction rate and negative prediction rate.The result is as shown in table 2.
Sensitivity (%)=A/ (A+C) * 100
Specificity (%)=D/ (D+B) * 100
Positive prediction rate (PPV) (%)=A/ (B+A) * 100
Negative prediction rate (NPV) (%)=D/ (D+C) * 100
Need to prove that the A to D in above-mentioned formula has following connotation:
The expression amount of the mRNA of A:ADAMTS4 (ADAMTS4/ beta-actin) belongs to high dose group, and is sorted into the case load of GR group;
The expression amount of B:ADAMTS4mRNA (ADAMTS4/ beta-actin) belongs to high dose group, and is sorted into the case load of NGR group;
The expression amount of C:ADAMTS4mRNA (ADAMTS4/ beta-actin) belongs to low dose group, and is sorted into the case load of GR group; And
The expression amount of D:ADAMTS4mRNA (ADAMTS4/ beta-actin) belongs to low dose group, and is sorted into the case load number of patients of NGR group.
Table 2
| Sensitivity | 40.0％ |
| Specificity | 94.4％ |
| PPV | 85.7％ |
| NPV | 65.4％ |
--second between GR group and NGR group be (ADAMTS5) relatively--
As index, to above-mentioned low dose group and above-mentioned high dose group, the classification that further is divided under the situation of GR group (reactivity is well organized) and NGR group (reactionless+moderate is reacted) is as shown in table 3 with the content of ADAMTS5.
Table 3
| ADAMTS5 | GR | NGR | Amount to |
| |
6 | 1 | 7 |
| Low dose group | 9 | 17 | 26 |
| Amount to | 15 | 18 | 33 |
x
2p＝0.016
Based on the classification shown in the table 3, by following formula meter sensitivity, specificity, positive prediction rate and negative prediction rate.The result is as shown in table 4.
Sensitivity (%)=E/ (E+G) * 100
Specificity (%)=H/ (H+F) * 100
Positive prediction rate (PPV) (%)=E/ (F+E) * 100
Negative prediction rate (NPV) (%)=H/ (H+G) * 100
Need to prove that E to H has following connotation in above-mentioned formula:
The expression amount of E:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to high dose group, and is sorted into the case load of GR group;
The expression amount of F:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to high dose group, and is sorted into the case load of NGR group;
The expression amount of G:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to low dose group, and is sorted into the case load of GR group; And
The expression amount of H:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to low dose group, and is sorted into the case load of NGR group.
Table 4
| Sensitivity | 40.0％ |
| Specificity | 94.4％ |
| PPV | 85.7％ |
| NPV | 65.4％ |
Can know from the result of table 2 and table 4; The expression amount (ADAMTS5/ beta-actin) of the expression amount of ADAMTS4mRNA (ADAMTS4/ beta-actin), ADAMTS5mRNA belongs under the situation of high dose group; Each that predict positive prediction rate (PPV) that it belongs to GR group is all up to 85.7%; Show with ADAMTS4 before the administration adalimumab or ADAMTS5 content and can predict drug effect rheumatoid arthritis as index.
--first between alleviation group (Re) and non-alleviation group (Nre) be (ADAMTS4) relatively--
As index,, further divide to go into the classification under the situation of alleviation group (Re) and non-alleviation group (Nre) as shown in table 5 with the content of ADAMTS4 to above-mentioned low dose group and high dose group.
Table 5
| ADAMTS4 | The alleviation group | Non-alleviation group | Amount to |
| High dose group | 4 | 3 | 7 |
| Low dose group | 3 | 23 | 26 |
| Amount to | 7 | 26 | 33 |
x
2p＝0.09
Based on the classification shown in the table 5, by following formula meter sensitivity, specificity, positive prediction rate and negative prediction rate.The result is as shown in table 6.
Sensitivity (%)=I/ (I+K) * 100
Specificity (%)=L/ (L+J) * 100
Positive prediction rate (PPV) (%)=I/ (J+I) * 100
Negative prediction rate (NPV) (%)=L/ (L+K) * 100
In above-mentioned formula, I to L has following connotation:
The expression amount of I:ADAMTS4mRNA (ADAMTS4/ beta-actin) belongs to high dose group, and is sorted into the case load of alleviation group;
The expression amount of J:ADAMTS4mRNA (ADAMTS4/ beta-actin) belongs to high dose group, and is sorted into the case load of non-alleviation group;
The expression amount of K:ADAMTS4mRNA (ADAMTS4/ beta-actin) belongs to low dose group, and is sorted into the case load of alleviation group; And
The expression amount of L:ADAMTS4mRNA (ADAMTS4/ beta-actin) belongs to low dose group, and is sorted into the case load of non-alleviation group.
Table 6
| Sensitivity | 57.1％ |
| Specificity | 88.5％ |
| PPV | 57.1％ |
| NPV | 88.5％ |
--second between alleviation group (Re) and non-alleviation group (Nre) be (ADAMTS5) relatively--
The content of ADAMTS5 is with index, to low dose group and high dose group, further divides to go into the classification under the situation of alleviation group (Re) and non-alleviation group (Nre), and is as shown in table 7.
Table 7
| ADAMTS5 | The alleviation group | Non-alleviation group | Amount to |
| High dose group | 5 | 2 | 7 |
| Low dose group | 2 | 24 | 26 |
| Amount to | 7 | 26 | 33 |
x
2p＝0.0003
Based on the classification shown in the table 7, by following formula meter sensitivity, specificity, positive prediction rate and negative prediction rate.The result is as shown in table 8.
Sensitivity (%)=M/ (M+O) * 100
Specificity (%)=P/ (P+N) * 100
Positive prediction rate (PPV) (%)=M/ (N+M) * 100
Negative prediction rate (NPV) (%)=P/ (P+O) * 100
In above-mentioned formula, M to P has following connotation:
The expression amount of M:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to high dose group, and is sorted into the case load of alleviation group;
The expression amount of N:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to high dose group, and is sorted into the case load of non-alleviation group;
The expression amount of O:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to low dose group, and is sorted into the case load of alleviation group; And
The expression amount of P:ADAMTS5mRNA (ADAMTS5/ beta-actin) belongs to low dose group, and is sorted into the case load of non-alleviation group.
Table 8
| Sensitivity | 71.4％ |
| Specificity | 92.3％ |
| PPV | 71.4％ |
| NPV | 92.3％ |
Can know from the result of table 6 and table 8; Be sorted under the situation of high dose group at the expression amount (ADAMTS4/ beta-actin) of ADAMTS4mRNA, the expression amount (ADAMTS5/ beta-actin) of ADAMTS5mRNA, the positive prediction rate (PPV) that is predicted as the alleviation group is respectively up to 57.1% (ADAMTS4), 71.4% (ADAMTS5).
In addition; Be sorted under the situation of low dose group at the expression amount (ADAMTS4/ beta-actin) of ADAMTS4mRNA, the expression amount (ADAMTS5/ beta-actin) of ADAMTS5mRNA; Negate for the negative prediction rate (NPV) of alleviation group (non-alleviation group) respectively up to 88.5% (ADAMTS4), 92.3% (ADAMTS5), quite high.
Above-mentioned expression as index, can predict whether the patient can be eased with the ADAMTS4 before the administration adalimumab or ADAMTS5 content.
--prediction 1: the DAS28 behind the administration adalimumab (ADAMTS4)--
The result of study of the relation of ADAMTS4mRNA expression amount (ADAMTS4/ beta-actin) and administration adalimumab 12 week back DAS28 (12w) in the preceding peripheral blood of Fig. 2 A demonstration administration adalimumab.
Shown in Fig. 2 A, ADAMTS4mRNA expression amount (ADAMTS4/ beta-actin) is negative correlation (r=-0.370) with the variation of administration adalimumab 12 week back DAS28 (12w) before the administration adalimumab.
That is to say; These results show; High more from ADAMTS4 content before the administration adalimumab in experimenter's the sample; Humanization anti-TNF alpha antibody drug is effective more to rheumatoid arthritis, and can quantification and predict the drug effect of 12 week of administration back humanization anti-TNF alpha antibody drugs based on ADAMTS4 content in the sample that comes the experimenter before the self administration of medication adalimumab.
--prediction 2: the DAS28 behind the administration adalimumab (ADAMTS5)--
ADAMTS5mRNA expression amount (ADAMTS5/ beta-actin) and the administration adalimumab result of study that the change of DAS28 (12w) concerns after 12 weeks in the preceding peripheral blood of Fig. 2 B demonstration administration adalimumab.
Shown in Fig. 2 B, ADAMTS5mRNA expression amount (ADAMTS5/ beta-actin) is negative correlation (r=-0.476) with the variation of administration adalimumab 12 week back DAS28 (12w) before the administration adalimumab.
That is to say; These results show; High more from ADAMTS5 content before the administration adalimumab in experimenter's the sample; Humanization anti-TNF alpha antibody drug is effective more to rheumatoid arthritis, and can quantification and predict the drug effect of 12 week of administration back humanization anti-TNF alpha antibody drugs based on ADAMTS5 content in the sample that comes the experimenter before the self administration of medication adalimumab.
Utilize possibility on the industry
Humanization anti-TNF alpha antibody drug of the present invention to the drug effect Forecasting Methodology of rheumatoid arthritis according to the ADAMTS4 that gives a certain moment before the said medicine and ADAMTS5 content one of at least, can safety high and predict that easily humanization anti-TNF alpha antibody drug is directed against the drug effect of rheumatoid arthritis; Mobility can also be predicted, in addition, thereby, therefore, medical diagnosis and treatment can be suitably be used for through the effective more really patient of said medicine administration can be evaded unnecessary spinoff to the rheumatoid arthritis after the said medicine.
Humanization anti-TNF alpha antibody drug of the present invention to the drug effect prediction unit of rheumatoid arthritis according to the ADAMTS4 that gives a certain moment before the said medicine and ADAMTS5 content one of at least, can safety high and predict that easily humanization anti-TNF alpha antibody drug is directed against the drug effect of rheumatoid arthritis; Mobility can also be predicted, in addition, thereby, therefore, medical diagnosis and treatment can be suitably be used for through the effective more really patient of said medicine administration can be evaded unnecessary spinoff to the rheumatoid arthritis after the said medicine.
Claims (8)
1. a humanization anti-TNF alpha antibody drug is characterized in that to the drug effect Forecasting Methodology of rheumatoid arthritis, comprises the steps:
Measurement is from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample; And
Whether as index, it is effective to said experimenter's rheumatoid arthritis to estimate said humanization anti-TNF alpha antibody drug with ADAMTS4 and ADAMTS5 content one of at least.
2. humanization anti-TNF alpha antibody drug according to claim 1 is to the drug effect Forecasting Methodology of rheumatoid arthritis, and wherein, said humanization anti-TNF alpha antibody drug is adalimumab (ADA).
3. humanization anti-TNF alpha antibody drug according to claim 1 and 2 is to the drug effect Forecasting Methodology of rheumatoid arthritis; Wherein, said is ADAMTS4mRNA and ADAMTS5mRNA expression amount one of at least from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample.
4. humanization anti-TNF alpha antibody drug according to claim 3 is to the drug effect Forecasting Methodology of rheumatoid arthritis, wherein, measures said ADAMTS4mRNA and ADAMTS5mRNA expression amount one of at least through the PCR in real time method.
5. a humanization anti-TNF alpha antibody drug is characterized in that to the drug effect prediction unit of rheumatoid arthritis, comprising:
Measuring unit, said measuring unit are measured the content one of at least from ADAMTS4 and ADAMTS5 in experimenter's the sample; And
Evaluation unit, whether as index, it is effective to said experimenter's rheumatoid arthritis to estimate said humanization anti-TNF alpha antibody drug with ADAMTS4 and ADAMTS5 content one of at least for said evaluation unit.
6. humanization anti-TNF alpha antibody drug according to claim 5 is to the drug effect prediction unit of rheumatoid arthritis, and wherein, said humanization anti-TNF alpha antibody drug is adalimumab (ADA).
7. according to claim 5 or 6 described humanization anti-TNF alpha antibody drugs drug effect prediction unit to rheumatoid arthritis; Wherein, said is ADAMTS4mRNA and ADAMTS5mRNA expression amount one of at least from the content one of at least of ADAMTS4 and ADAMTS5 in experimenter's the sample.
8. humanization anti-TNF alpha antibody drug according to claim 7 is to the drug effect prediction unit of rheumatoid arthritis, wherein, measures said ADAMTS4mRNA and ADAMTS5mRNA expression amount one of at least through the PCR in real time method.
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| JP2009266539A JP5399219B2 (en) | 2009-11-24 | 2009-11-24 | Method and apparatus for predicting the efficacy of human anti-TNFα antibody for rheumatoid arthritis |
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| PCT/JP2010/068909 WO2011065168A1 (en) | 2009-11-24 | 2010-10-26 | Method and apparatus for prediction of pharmacological efficacy of humanized anti-tnfα antibody drug on rheumatoid arthritis |
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| KR101593065B1 (en) * | 2015-07-30 | 2016-02-12 | (주)바이오리드 | Method of predicting efficancy of t cell selective costimulation modulator and device |
| WO2017199418A1 (en) * | 2016-05-20 | 2017-11-23 | 株式会社ケイティーバイオ | Adamts5 gene quantification method, primer pair, combination of primer pair and probe, and kit |
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| WO2002031163A1 (en) * | 2000-10-11 | 2002-04-18 | Kazusa Dna Research Institute Foundation | Novel adamts family polypeptide and gene encoding the same |
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| WO2010038840A1 (en) * | 2008-10-03 | 2010-04-08 | Tsuzaka Kensei | METHOD FOR PREDICTING PHARMACOLOGICAL EFFICACY OF ANTI-TNFα ANTIBODY PREPARATION ON RHEUMATOID ARTHRITIS, AND PHARMACOLOGICAL EFFICACY PREDICTION APPARATUS |
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| WO2002031163A1 (en) * | 2000-10-11 | 2002-04-18 | Kazusa Dna Research Institute Foundation | Novel adamts family polypeptide and gene encoding the same |
| CN101039959A (en) * | 2004-06-30 | 2007-09-19 | 杜门蒂斯有限公司 | Compositions and methods for treating inflammatory disorders |
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| Title |
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| 津坂憲政等: "投与前血中ADAMTS5発現量をもとにしたRAに対するインフリキシマブ有効性予測", 《日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集》 * |
| 津坂憲政等: "投与前血中ADAMTS5発現量をもとにしたRAに対するインフリキシマブ有効性予測", 《日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集》, vol. 5318, 19 March 2009 (2009-03-19) * |
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| WO2011065168A1 (en) | 2011-06-03 |
| US20120231460A1 (en) | 2012-09-13 |
| CN102639715B (en) | 2014-09-10 |
| JP5399219B2 (en) | 2014-01-29 |
| EP2505662A1 (en) | 2012-10-03 |
| RU2511394C2 (en) | 2014-04-10 |
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| EP2505662A4 (en) | 2013-12-25 |
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